1-Substituted-3,5-dipyridyl-1,2,4-triazoles

ABSTRACT

Compounds useful in the treatment of asthma, the symptoms of allergy and in some instances in gout and hyperuricemia are described. The novel compounds are 1-substituted-1,2,4-triazoles being additionally substituted at the 3- and 5-positions with a pyridyl radical. Methods of preparing these tri-substituted triazoles are described.

United States Patent 11 1 Baldwin et al.

[ May6, 1975 l l-SUBSTITUTED-3,S-DIPYRIDYL-l ,2,4-

TRIAZOLES [75] Inventors: John J. Baldwin, Lansdale;

Frederick C. Novello, Berwyn, both [21] Appl. No.: 361,914

[52] US. CL. 260/296 R; 260/2475 R; 260/293.69; 260/294.9; 260/295 R;424/248; 424/263,

[51] Int. Cl C07d 31/42 [58] Field of Search 260/296 R, 308 R, 295 AM[56] References Cited UNITED STATES PATENTS 3,308,131 3/1967 McKusick260/293.69

FOREIGN PATENTS OR APPLICATIONS 1,092,359 11/1954France.....................,.......... 260/308 1,238,943 7/1960France.... 260/308 4,840 2/1967 France 260/308 OTHER PUBLICATIONSGeldard et al., J. Org. Chem. Vol. 30(1) pp. 318-319, (1965).

Kubota et al., Chem. Abstracts, Vol. 58, pp. 2449a, (1963).

Roberts et al., Basic Principles of Organic Chemistry, BenjaminPublishers, Page 806, (I965) OD 251 R 58 C6.

Primary Examiner-Alan L. Rotman Attorney, Agent, or Firm.l. JeromeBehan; Daniel T. Szura [57] ABSTRACT Compounds useful in the treatmentof asthma, the symptoms of allergy and in some instances in gout andhyperuricemia are described. The novel compounds arel-substituted-1,2,4-triazoles being additionally substituted at the 3-and 5-p0sitions with a pyridyl radical. Methods of preparing thesetri-substituted triazoles are described.

10 Claims, No Drawings 1 l-SUBSTITUTED-3,S-DIPYRIDYL-l ,2,4-

TRIAZOLES FIELD OF THE INVENTION The invention relates to certainl,2,4triazoles trisubstituted in the l, 3 and positions, which areprincipally useful in the alleviation of symptoms of asthma and allergyas well as, in some instances, in the treatment of gout and asanti-hyperuricemic agents.

The trisubstituted-l,2,4-triazole compounds of this invention have beenfound in animal studies to inhibit bronchial constriction induced byhistamine and other constricting agents and are therefore useful asbronchodilating agents in the treatment of asthma and allergy. Asbronchodilating agents, the products of this invention have been foundto have relatively low chronotropic effect as compared with knownbronchial dilator agents. Additionally, some of the products possessuseful xanthine oxidase inhibiting properties, and are therefore usefulin the treatment of gout and as anti-hyperuricemic agents, and someexhibit antihyper tensive properties.

SUMMARY OF THE INVENTION The novel compounds of this invention have thestructure represented by Formulas I and la N R TN "L fl- 3 N R I Iawherein R, represents a substituted lower alkyl (C, wherein thesubstituent is selected from one or more of the groups hydroxy, phenyl,halophenyl (especially chlorophenyl), nitrophenyl, sulfamoylphenyl(especially N,N-di(C,. -alkyl) sulfamoylphenyl), tertiary amino(especially di-C,. -alkylamino, piperidino, morpholino, pyridyl [2, 3 or4]) carboxy, and cyano; and R and R may be the same or different andseparately represent 2, 3 or 4pyridyl. Also useful for the same purposeare the pharmaceutically acceptable nontoxic acid salts of suchcompounds, the salts being of the pyridine ring present in the molecule.

The preferred compounds of this invention are those of Formulas I and laabove wherein R, is phenalkyl or substituted phenalkyl where thesubstituent preferably is N,N-dialkylsulfamoyl and the alkyl moietycontains l carbon atom and R and R separately represent 4- pyridyl.

Included within the scope of the invention are the pharmaceuticallyacceptable acid addition salts, examples being the hydrochlorides,sulfates, tartrates, oxalates and the like.

The compounds of Formulas l and la can be prepared by reacting thedesired preformed 3,5-di-pyridyltriazole with an appropriate alkylatingagent. Where R and R are dissimilar substituents, a mixture of compoundsis obtained, i.e., the R, substituent may be substituted on either oneof the adjacent nitrogens in the triazole ring. Alkylation is achievedby reacting the sodium salt of the triazole with an alkylating agentsuch as, for example, a substituted alkyl halide having the formula R,-halide preferably the chloride, bromide or iodide.

The following examples are given for the purpose of illustration and notby way of limitation.

EXAMPLE I l-( 2-Cyanoethyl )-3,5-bis(4-pyridyl)- l ,2,4-triazoleAcrylonitrile (I g.) is added to 3,5-bis (4-pyridyl) 1.2,4-triazole (l.lg.) in pyridine (5 ml.). Five drops of triton B (N-benzyltrimethylammonium hydroxide) is added and the mixture heated at reflux for 2.5hours. The solution is concentrated and the resulting solid isrecrystallized from acetonitrile to yield 375 mg. of l-(2-cyanoethyl)-3,5-bis (4-pyridyl)-l ,2,4-triazole melting at l60 l 6 l.5C.

EXAMPLE 2 l-(2-Cyanoethyl)-3,5-bis (3-pyridyl)-l ,2,4-triazole When3,5-bis (3-pyridyl)l,2,4triazole is used in the process of Example I inplace of 3,5-bis (4-pyridyl)- 1,2,4-triazole, l-( 2-cyanoethyl )-3,5-bis( 3-pyridyl l,2,4-triaz0le is obtained melting at l45l47C.

EXAMPLE 3 l-( Z-Carboxyethyl )-3,5bis( 4-pyridyl l ,2,4triazolel-(2-Cyanoethyl)-3,5-bis (4-pyridyl)-l,2,4-triazole (l g.) is dissolvedin concentrated hydrochloric acid 10 ml.) and the resulting solution isheated 4 hours on a steam bath. The reaction mixture is concentrated toa solid which is dissolved in water and the solution neutralized withaqueous ammonia. A solid separates and is recrystallized fromacetonitrile-water yielding 0.6 g. of l-( 2carboxyethyl)-3,5-bis(4-pyridyl)-l ,2,4-triazole melting at 245246.5C.

EXAMPLE 4 l-Benzyl-3,5-bis (4-pyridyl )-l ,2,4-triazole To 3,5-bis(4-pyridyl)-l ,2,4-triazole (4.4 g., 0.02m0l) in dry tetrahydrofuran(200 ml.) is added 57% sodium hydride in mineral oil (1 g, 0.024 mol.)and the mixture is heated 45 minutes at reflux. The suspension isconcentrated to a solid, N,N-dimethylformamide ml.) and benzyl chloride(2.8 g., 0.022 mol.) are added. The mixture is stirred 0.5 hour atambient temperature followed by 4 hours at steam bath temperature. Thesolution is concentrated to a gum, water is added and the materialsolidifies. After recrystallization from methylcyclohexane 1.4 g. of1-benzyl-3,5- bis (4-pyridyl)-l ,2,4-triazole, melting at l36l 38C. isobtained.

EXAMPLES 5-] 7 Following substantially the same procedure described inExample 4, but replacing the benzyl chloride by an equivalent quantityof the alkylating agent identified in column 2 of the following table,the l-R,-3,5-bis (4-pyridyl)-l ,2,4triazole compound having the R,substituent identified in column 3 is obtained.

Example No. Alkylating Agent l m. C.

5 BrCH S N((2 11 -CH2-@SO2N(C3H7) 2 103-106 6 ClCH --N0 CH2@N02 191-1927 Bit-CH -CH2-@ 131-132 c1 c1 8 c1-cu of 411 -6} 160-161 9 Cl-CH -N -cH193-194 10 on on on on Cl-GH -c':n-cn -cn Janna'lso 11 c1-ca -@-c1 -cH-@-c1 165l66.5

12 Br-CH CH CH OH -CH2-CH2CH2-OH 123-126 13 BICH2CH20H -CH2CH2-OH 209 -25 l 1 c1-ca -ca 3 -cH -cu J 121-123 15 CICHZCHZN (c 11 2 CH2CH2N (c 11 293-94. 3

l6 c1cn -cH -CH2CH2NH 75-76.5

17 Brcn c11 CH2CH2@ 116 The invention further provides pharmaceuticalcompositions comprising, as active bronchodilating agent, at least oneof the compounds according to the invention in association with apharmaceutical carrier or excipient to which other active ingredientscan be added, if desired. The product or products can be presented in aform suitable for administration orally (such as capsules, tablets orliquid preparations), or for parenteral administration (in the form ofsolutions or suspensions) or in aerosols prepared by conventionalmethods. For example, a capsule can be prepared by conventional methodsemploying lactose as an cxcipient and containing per unit dosage 10-25mgs. of active compound. Unit dosages can range between about 5 to 100mg. for administration as prescribed by the physician.

While this invention has been illustrated by certain specific members ofthe novel 1,3,5-trisubstituted- 1,2,4-triazole products made by certainspecific methods and formulated into certain specific dosage forms, itis to be understood that the invention is not to be considered limitedby or to the specific embodiments illustrated but is to encompass othermembers of the novel products falling within the scope of the genericdisclosure and claims as well as other methods or modifications of themethods described for their preparation and other formulations, all ofwhich would be obvious in view of the teaching herein to one skilled inthe art,

What is claimed is:

l. A triazole of the formula 5. A triazole of claim 2 wherein R is 6. Atriazole of claim 2 wherein R is -CH CHOH--CH OH 7. A triazole of claim2 wherein R is 8. A triazole of claim 2 wherein R is --CH CH-- l0.Pharmaceutically acceptable acid addition salts of the triazoles ofclaim 1.

2. A triazole as claimed in claim 1 wherein R3 and R5 each represent4-pyridyl.
 3. A triazole as claimed in claim 1 wherein R1 is benzyl; andR3 and R5 each represent 4-pyridyl.
 4. A triazole of claim 2 wherein R1is
 5. A triazole of claim 2 wherein R1 is
 6. A triazole of claim 2wherein R1 is -CH2-CHOH-CH2OH
 7. A triazole of claim 2 wherein R1 is 8.A triazole of claim 2 wherein R1 is -CH2-CH2-N(C2H5)2.
 9. A triazole ofclaim 2 wherein R1 is selected from -CH2-CH2-OH and -CH2-CH2-CH2-OH. 10.Pharmaceutically acceptable acid addition salts of the triazoles ofclaim 1.